A goal of molecular imaging is to produce quantitative maps of the distribution of a particular tracer or endogenous substance with the resolution characteristic of the chosen method of detection. For this to be accomplished, a quantitative relationship must exist between an image parameter and the imaging agent's concentration. Magnetic resonance imaging (MRI) has been successful in medicine due to the richness of the set of spin manipulations that introduce specific contrast variations in tissue.
The range of applications of MRI has been expanded through the discovery and usage of agents that introduce image contrast via perturbations of the magnetic relaxation rates of nearby nuclei. MRI contrast is a complex, non-linear function of the concentration of contrast agents on nuclear relaxation rates. However, as long as these non-linearities give rise to single-valued, monotonic dependences of contrast on the agent concentration, it is possible to anticipate these nonlinear effects through theory and then to use these relationships to measure the concentration of a given contrast agent in a particular imaging slice.
A useful class of MRI contrast agents, that may be used with the present invention, is comprised of superparamagnetic iron oxide nanoparticles (SPIONs) which are widely used as complexes containing, in addition to the iron oxide core, one or more recognition ligands, such as antibodies, peptides, aptamers, or small molecules. These recognition ligands confer binding specificity on the interaction between the SPION and a target epitope in the tissue. SPION nanoparticles may be constructed which are loaded with therapeutic molecules such as drugs, microRNAs, or enzymes, in order to exploit their specific interactions with target cells.
In this manner, SPIONs as well as other contrast agents, become both diagnostic and therapeutic by being able to accurately determine their concentrations in the target tissues. For example, one of the primary impediments to the treatment of primary or metastatic brain tumors is that most chemotherapeutic antitumor drugs do not cross the blood-brain barrier in sufficient quantity to achieve a therapeutic concentration in the brain parenchyma. This problem is further confounded by the dearth of facile, non-invasive methods for determining the actual, in vivo drug concentrations in tissues.
In addition, using knowledge of cell surface receptor density for the particle-targets, one may be able to determine, for example, the number of tumor or other cells (such as macrophages) in a measured volume from the iron concentration measurements. The MRI signal perturbation by the SPIONs, as well as other contrast agents, properly understood, would then serve as a reporter for the ligand's epitope density. Current MRI in humans enjoys submillimeter resolution so that tumor burden could be measured with good accuracy by these means. The time-dependent movement and transport of nanoparticles could also be determined because repeated MR images are essentially harmless and well-tolerated by people.
Since SPIONs are observable using MRI, an MRI method for measuring the concentration of nanoparticles in tissues would provide a solution for many of these important problems, because, if one knew the easily-measured relationship between drug and iron concentrations in the SPIONs, the measurement of the [Fe] in the tissue would become a surrogate for the [drug].